Ph-activated nanoparticles

Abstract

Disclosed herein is a pH activated nanoparticle that can be used to deliver labile therapeutic or diagnostic agents to the cytoplasm of cells. These nanoparticles allow the agents to escape the endosome by releasing a gas in an amount effective to disrupt the endosome and release the agents into the cytoplasm. The disclosed nanoparticles have a shell, such as a phospholipid bilayer shell, and a core containing a gas bound to a substrate by a pH sensitive interaction. Also disclosed herein is are methods for delivering a pH sensitive cargo to the cytoplasm of a cell, treating triple negative breast cancer (TNBC) in a subject, and treating HER2+ breast cancer in a subject.

1 . A pH activated nanoparticle, comprising
 a shell comprising a phospholipid bilayer, and   a core comprising a gas bound to a substrate by a pH sensitive interaction.   
     
     
         2 . The nanoparticle of  claim 1 , wherein the substrate comprises chitosan-guanidine (CG) or chitosan-arginine (CA). 
     
     
         3 . The nanoparticle of  claim 1 , wherein the substrate comprises metformin. 
     
     
         4 . The nanoparticle of  claim 1 , wherein the substrate comprises calcium carbonate. 
     
     
         5 . The nanoparticle of  claim 1 , wherein the gas comprises carbon dioxide. 
     
     
         6 . The nanoparticle of  claim 1 , wherein the core further comprises a pH sensitive therapeutic or diagnostic agent. 
     
     
         7 . The nanoparticle of  claim 6 , wherein the pH sensitive therapeutic or diagnostic agent is an RNA or DNA oligonucleotide. 
     
     
         8 . The nanoparticle of  claim 7 , wherein the pH sensitive therapeutic or diagnostic agent is an mRNA, ncRNA, siRNA, miRNA, or shRNA oligonucleotide. 
     
     
         9 . The nanoparticle of  claim 6 , wherein the pH sensitive therapeutic or diagnostic agent is peptide. 
     
     
         10 . The nanoparticle of  claim 6 , wherein the pH sensitive therapeutic or diagnostic agent is a labile small molecule. 
     
     
         11 . The nanoparticle of  claim 7 , wherein the pH sensitive therapeutic agent is a POLR2A-targeting siRNA (siPol2). 
     
     
         12 . The nanoparticle of  claim 7 , wherein the pH sensitive therapeutic agent is an anti-miR-21 oligonucleotide. 
     
     
         13 . The nanoparticle of  claim 12 , further comprising a small molecule inhibitor against WIP1. 
     
     
         14 . The nanoparticle of  claim 13 , wherein the small molecule inhibitor against WIP1 comprises GSK2830371. 
     
     
         15 . The nanoparticle of  claim 1 , further comprising paclitaxel, camptothecin, doxorubicin, or any combination thereof. 
     
     
         16 . The nanoparticle of  claim 1 , wherein the phospholipid bilayer comprises dipalmitoyl phosphatidylcholine (DPPC) or dioleoyl phosphatidylcholine (DOPC). 
     
     
         17 . The nanoparticle of  claim 1 , wherein the shell further comprises poly(lactic-co-glycolic acid) (PLGA). 
     
     
         18 . The nanoparticle of  claim 17 , wherein the PLGA is PEGylated. 
     
     
         19 . The nanoparticle of  claim 1 , wherein the shell further comprises a poloxamer. 
     
     
         20 . The nanoparticle of  claim 19 , wherein the poloxamer is poloxamer 407. 
     
     
         21 . A method for treating triple negative breast cancer (TNBC) in a subject, comprising administering to the subject a therapeutically effective amount of the pH activated nanoparticle of  claim 11 . 
     
     
         22 . The method of  claim 21 , wherein the TNBC has a TP53 gene mutation or deletion. 
     
     
         23 . A method for delivering a pH sensitive cargo to the cytoplasm of a cell, comprising loading the pH sensitive cargo into the pH activated nanoparticle of  claim 1 , and contacting the cell with the loaded nanoparticle. 
     
     
         24 . A method for treating HER2+ breast cancer in a subject, comprising administering to the subject a therapeutically effective amount of an anti-miR-21 oligonucleotide and a small molecule inhibitor against WIP1. 
     
     
         25 - 32 . (canceled)